Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000419.4(ITGA2B):c.2602-3C>G

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA10575472

2893 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1081b492-a008-4ae5-93b9-c5a81d6b86e0

Approved on: 2023-09-07

Published on: 2023-09-21

HGVS expressions

NM_000419.4:c.2602-3C>G

NM_000419.4(ITGA2B):c.2602-3C>G

NC_000017.11:g.44375719G>C

CM000679.2:g.44375719G>C

NC_000017.10:g.42453087G>C

CM000679.1:g.42453087G>C

NC_000017.9:g.39808613G>C

NG_008331.1:g.18787C>G

ENST00000262407.6:c.2602-3C>G

ENST00000648408.1:c.2033-3C>G

ENST00000262407.5:c.2602-3C>G

ENST00000587295.5:c.253+114C>G

ENST00000592462.5:n.1397-3C>G

NM_000419.3:c.2602-3C>G

NM_000419.5:c.2602-3C>G

NM_000419.5(ITGA2B):c.2602-3C>G

Likely Pathogenic

PM4 PM3 PM2_Supporting PP4_Strong

BP7

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.4:c.2602-3C>G variant is a splice region variant that is predicted to result in abnormal splicing and is shown to skip exon 26 in RNA studies from a patient (PMID: 1317725), resulting in an in-frame deletion of Val868 to Val909 (3.9% of the protein; PM4). It occurs at a low frequency in gnomADv2.1.1 with a MAF of 0.00006523 in the East Asian population (PM2_supporting). At least 3 compound heterozygous probands are reported in the literature, with the other variants being Leu973AlafsTer63, Leu214Pro, and Ala777Asp (PMID: 15748238, PMID: 27696190, PMID: 29675921; PM3). In summary, based on the available evidence at this time, the c.2602-3C>G variant is classified as likely pathogenic. GT-specific criteria applied: PM2_supporting, PM3, PM4, PP4_strong.

PM4

The variant is shown to cause the loss of 42 amino acids that constitute exon 26. The in-frame deletion of exon 26 is counted as evidence meeting criteria for PM4.

PM3

This variant has been identified in a compound heterozygote with Leu214Pro from PMID: 27696190, which has been classified as Pathogenic by the ClinGen Platelet Disorders VCEP; however, it is not confirmed in trans with this splice site variant. 0.5 pts PMID: 15748238 describes a compound heterozygous patient with pathogenic variant Leu973Alafs confirmed in trans with c.2602-3C>G by sequencing of patient cDNA clones. 1pt PMID: 29675921 describes a compound heterozygous patient with VUS Ala777Asp not confirmed in trans. 0pt TOTAL 1.5pt

PM2_Supporting

The prevalence is 1/15330 alleles in gnomAD, which is less than 1/10,000; therefore, PM2 is met.

PP4_Strong

Two probands from PMIDs: 15748238 and 27696190 meet criteria for PP4 including bleeding phenotypes and impaired aggregation with all agonists except ristocetin. Patient GT30 of PMID: 29675921 meets the criteria for PP4_Moderate; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

BP7

c.2602-3C>G is a splice region variant that is predicted to result in abnormal splicing and is shown to skip exon 26 in RNA studies from a patient (PMID: 1317725).

Curation History

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